Lym. Phoid Enhancer Factor 1 Directs Hair Folhcle Patterning and Epithelial

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Lym. Phoid Enhancer Factor 1 Directs Hair Folhcle Patterning and Epithelial Lym.phoid enhancer factor 1 directs hair folhcle patterning and epithelial cell fate Pengbo Zhou, Carolyn Byrne, Jennifer Jacobs, and Elaine Fuchs 1 Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois 60637 USA T cell-specific transcription factor (TCF-1) and lymphoid enhancer factor 1 (LEF-1) have been implicated exclusively in the regulation of T cell-specific genes. The only adult tissue other than thymus known to express these factors is spleen and lymph node, which contain low levels of LEF-1 and no TCF-1. We noticed that genes involved in hair-specific gene expression possess LEF-I/TCF-1 consensus motifs located in similar positions relative to their TATA box. We show that of the two factors only LEF-1 is expressed in hair follicles; it can be cloned in both splice forms from human skin keratinocytes and it can bind to these sites in the hair promoters. We show that LEF-1 mRNA is present in pluripotent ectoderm, and it is up-regulated in a highly restricted pattern just before the formation of underlying mesenchymal condensates and commitment of overlying ectodermal cells to invaginate and become hair follicles. New waves of ectodermal LEF-1 spots appear concomitant with new waves of follicle morphogenesis. To test whether LEF-1 patterning might be functionally important for hair patterning and morphogenesis, we used transgenic technology to alter the patterning and timing of LEF-1 over the surface ectoderm. Striking abnormalities arose in the positioning and orientation of hair follicles, leaving a marked disruption of this normally uniform patterning. This provides the first direct evidence that ectodermal cues are critical in establishing these developmental processes, which at later stages are known to be influenced by underlying mesenchyme. Remarkably, elevated LEF-1 in the lip furrow epithelium of developing transgenic animals triggered these cells to invaginate, sometimes leading to the inappropriate adoption of hair follicle and tooth cell fates. Collectively, our findings demonstrate that ectodermal expression of LEF-1 plays a central role in gene expression, pattern formation, and other developmental processes involving epithelial-mesenchymal associations. [Key Words: LEF-1; TCF- 1; transcription factors; hair follicle morphogenesis; keratin gene regulation] Received September 28, 1994; revised version accepted February 8, 1995. T cell-specific transcription factor (TCF-1) and lymphoid lines (Travis et al. 1991; van de Wetering et al. 1991; enhancer factor (LEF-1) are recently isolated transcrip- Waterman et al. 1991). During embryogenesis, TCF-1 tion factors that contain a DNA-binding sequence ho- and LEF-1 mRNAs are expressed more broadly and some- mologous to the high mobility group (HMG) motif, an times differentially (Oosterwegel et al. 1993). In the de- -80 amino acid domain conserved in the HMG proteins veloping thymus, TCF-1 is induced just before T cell- (Travis et al. 1991; van de Wetering et al. 1991). Both specific gene expression. On the other hand, LEF-1 TCF-1 and LEF-1 contain a high degree of homology in mRNAs are expressed less abundantly and more uni- their HMG domains, and both recognize the core con- formly throughout T-cell development, suggesting that sensus motif 5'-CTTTGA/TA/T-3', located in the en- its function might differ from that of TCF-1. hancers of a number of genes expressed at early stages of DNA binding by LEF-1 has been shown to involve an T-cell development (Travis et al. 1991; van de Wetering interaction with the minor groove, and it invokes a sharp et al. 1991; Waterman et al. 1991; Giese et al. 1991, bend in the DNA helix (Giese et al. 1991, 1992). It has 1992; Giese and Grosschedl 1993). Both factors exist in been postulated that LEF-1 and TCF-1 may exert their alternative splicing forms, but all forms bind to the same effects by bringing other DNA-bound transcription fac- sequence, making the functional significance of this tors closer to one another, thereby facilitating their as- multiplicity unclear (Travis et al. 1991; van de Wetering sociation. Thus, these factors have been implicated in et al. 1991, 1992). the structural modeling of chromatin, rather than func- All forms of TCF-1 and LEF-1 mRNAs have been de- tioning as conventional transcriptional activators. This tected in adult thymus and various T-cell culture lines, said, non-HMG transcriptional activation has also been but not in other adult nonlymphoid tissues or non-T-cell noted (Carlsson et al. 1993). Our focus on LEF-1 began from an interest in the reg- ~Corresponding author. ulation of the genes involved in hair follicle morphogen- 700 GENES& DEVELOPMENT 9:570-583 1995 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/95 $5.00 Hair morphogenesis, gene expression, and LEF-1 esis and differentiation. A number of genes have been follicles, we engineered a transgene to misregulate the cloned that encode hair-specific keratins, the major levels and timing of expression of LEF-1 during skin em- structural proteins of the hair shaft (Heid et al. 1986; for bryogenesis in mice. We show that these mice have gross review, see Rogers and Powell 1993). Although little is abnormalities in the positioning and angling of their hair known about the precise mechanisms underlying the follicles, processes previously assumed, although never regulation of any of these genes, a number of potential demonstrated, to be controlled by mesenchyme. More- regulatory motifs have been identified on the basis of over, the elevated levels of LEF-1 seem to create confu- sequence comparisons (McNab et al. 1989; Powell et al. sion within the biochemical programs that allow oral 1991, 1992; Rogers and Powell 1993). One of these sites, epithelial cells to select their cell fates. In some cases, 5'-CTTTGAAGA-3', referred to as the HK-1 motif, was this results in an incorrect fate choice, leading to hairs detected in four published hair keratin promoters (Pow- and teeth protruding from inappropriate sites in the ell et al. 1991; Rogers and Powell 1993). The similarities gums. Our findings have important implications for un- between the HK-1 sequence motif and the LEF-1/TCF-1 derstanding hair and tooth development and the role of motif prompted us to explore the possibility that these LEF-1 in these complex processes. transcription factors may be involved in regulation of hair morphogenesis and gene expression. In this report, we show that LEF-1 motifs are present Results in 13 of 13 published hair keratin promoters, and that the Hair follicle differentiation and the widespread motifs often reside between 180 and 250 bp 5' from the presence of LEF-1/TCF-1 motifs in hair keratin TATA box. We show that LEF-1 binds hair keratin pro- promoters moters in vitro, and that LEF-1 is present during skin development in ectoderm that will express these pro- Epidermis, hairs, and nails are all derived embryologi- moters as the cells differentiate. In addition, we show cally from a common precursor, the ectoderm (Fig. 1; that LEF-1 concentrates at regions where underlying Hardy 1992). In the adult hair follicle, differentiation is mesenchymal condensates will form and initiate epithe- complex (Fig. 1). The hair is surrounded by two sheaths, lial-mesenchymal interactions prerequisite to hair folli- an outer root sheath contiguous with the epidermis but cle morphogenesis. To test the possibility that the pat- thought to have its own compartment of stem cells terning of ectodermally derived LEF-1 is involved func- (Rochat et al. 1994), and an inner root sheath, whose tionally in the determination and morphogenesis of hair cells are derived from the same precursors as the hair LEF-I/TCF-1 CONSENSUS BINDING SITE: 5' -C T T T G A/T A/T -3' PUTATIVE LEF-I/TCF-I BINDING SITES ~N HAIR-SPECIFIC KERATIN GENES EXPRESSED IN THE CORTEX: 9 . -220 G C A C T T T G A A G A T G A A A C A T -201 sKII9 (IF) -189 C G G C T T T G A A G A T G A A A C A G -170 sKIII0 (IF) 247 C T T C T T T G A A G G G C C A C C G C -228 mHKAIb (IF) -239 G C C C T T T G A A G C C A G A C C A T -220 sKI (47.6kDa) (IF) -270 C T C C T T T G T A C G T A G A A C C T -251 mHKAIa (IF) -191 A C C A T C A A A G A A C G A G C C A C -172 mB2A (HS) -303 G C T A T C A A A G G A C A T T T A T G -284 sB2A (HS) -255 G C T C T T T G A A C A T G G A A A A C -236 sB2D (HS) -247 T A A T A C A A A G G C T G A G A C T T -228 sB2C (HS) -200 T C A A A C A A A G G T T A A T T A G G -181 sBIIIB4 (HS) -235 G G G C T T T G A A G A C T C T G C A A -216 sHGTI-F (HGT) -199 T G A C T T T G A A G A T A C A A C A C -180 sHGTI-C2 (HGT) -178 T G C C T C A A A G T C A A C A A A G G -159 cKERI (HGT) Figure 1.
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